Chemokine (C-C motif) receptors in fibrogenesis and hepatic regeneration following acute and chronic liver disease.
Chemokine (C-C motif) receptors in fibrogenesis and hepatic regeneration following acute and chronic liver disease.
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DOI：
10.1002/hep.23338
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发表时间：
2009-11-01
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影响因子：
--
通讯作者：
Ramm, Grant A
中科院分区：
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作者：
Ramm, Grant A
肝纤维化是对慢性肝损伤的反应，几乎完全发生在促炎环境中。然而，炎症介质在肝脏纤维化反应中的作用知之甚少。因此，我们研究了CC趋化因子及其受体在肝纤维化中的作用。CC趋化因子MIP-1α、MIP-1β和RANTES及其受体CCR 1和CCR 5在2种实验性纤维化小鼠模型中均强烈上调。通过广谱CC趋化因子抑制剂35 k中和CC趋化因子有效地减少了肝纤维化，并且CCR 1和CCR 5缺陷小鼠显示出显著减少的肝纤维化和巨噬细胞浸润。CCR 1和CCR 5嵌合小鼠的纤维化分析显示，CCR 1介导其在BM衍生细胞中的促纤维化作用，而CCR 5介导其在常驻肝细胞中的促纤维化作用。CCR 5通过氧化还原敏感性、PI 3 K依赖性途径促进肝星状细胞（HSC）迁移。CCR 5缺陷的HSC和CCR 1和CCR 5缺陷的Kupffer细胞都表现出对CC趋化因子诱导的迁移的强烈抑制。最后，我们在肝硬化患者中检测到RANTES、CCR 1和CCR 5的显著上调，证实了CC趋化因子系统在人类纤维化中的激活。因此，我们的数据支持CC趋化因子系统在肝纤维化中的作用，并表明CCR 1和CCR 5在枯否细胞和HSC中的不同作用。
Hepatic fibrosis develops as a response to chronic liver injury and almost exclusively occurs in a proinflammatory environment. However, the role of inflammatory mediators in fibrogenic responses of the liver is only poorly understood. We therefore investigated the role of CC chemokines and their receptors in hepatic fibrogenesis. The CC chemokines MIP-1α, MIP-1β, and RANTES and their receptors CCR1 and CCR5 were strongly upregulated in 2 experimental mouse models of fibrogenesis. Neutralization of CC chemokines by the broadspectrum CC chemokine inhibitor 35k efficiently reduced hepatic fibrosis, and CCR1-and CCR5-deficient mice displayed substantially reduced hepatic fibrosis and macrophage infiltration. Analysis of fibrogenesis in CCR1-and CCR5-chimeric mice revealed that CCR1 mediates its profibrogenic effects in BM-derived cells, whereas CCR5 mediates its profibrogenic effects in resident liver cells. CCR5 promoted hepatic stellate cell (HSC) migration through a redox-sensitive, PI3K-dependent pathway. Both CCR5-deficient HSCs and CCR1-and CCR5-deficient Kupffer cells displayed strong suppression of CC chemokine–induced migration. Finally, we detected marked upregulation of RANTES, CCR1, and CCR5 in patients with hepatic cirrhosis, confirming activation of the CC chemokine system in human fibrogenesis. Our data therefore support a role for the CC chemokine system in hepatic fibrogenesis and suggest distinct roles for CCR1 and CCR5 in Kupffer cells and HSCs.